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Bioorg Med Chem Lett. 2011 May 15;21(10):2836-9. doi: 10.1016/j.bmcl.2011.03.081. Epub 2011 Mar 31.

The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.

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1
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1.

Abstract

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.

PMID:
21507640
DOI:
10.1016/j.bmcl.2011.03.081
[Indexed for MEDLINE]

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